Small extracellular vesicles derived from Nrf2-stimulated bone marrow mesenchymal stem cells ameliorated the testis damage and fertility disorder in doxorubicin-treated mice

IF 3.3 4区医学 Q2 REPRODUCTIVE BIOLOGY

Reproductive toxicology Pub Date : 2025-02-01 DOI:10.1016/j.reprotox.2025.108847

Maryam Taher, Hanieh Jalali, Homa Mohseni Kouchesfehani

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引用次数: 0

Abstract

Bone marrow mesenchymal/stromal stem cell (BMSC)-derived small extracellular vesicles (sEVs) are promising therapeutic agents owing to their low immunogenicity and ability to cross biological barriers. Doxorubicin (DOX), a common chemotherapeutic agent, damages testicular tissue. This study aimed to enhance the antioxidant activity of sEVs by activating the Nrf2 gene in BMSCs and evaluate their therapeutic potential for DOX-induced fertility disorders. Testicular damage was induced by DOX in NMRI mice. BMSCs from Wistar rats were treated with Bardoxolone methyl (BaMet) to upregulate Nrf2. The sEVs were isolated through differential ultracentrifugation and validated for size, morphology, and protein expression. The antioxidant activity was assessed using specific kits. sEVs containing 10 μg of proteins were injected intravenously into DOX-injured mice. After 35 days, the testes were collected for histopathological, hormonal, and immunological analyses, along with the evaluation of sperm parameters. Male and female mice were paired to determine the pregnancy rates. BaMet-sEVs exhibited higher antioxidant activity and significantly improved serum testosterone levels, testicular cell populations, sperm viability, and motility in DOX-injured mice. In addition, BaMet-sEVs treatment enhanced fertility and increased the number of offspring. This study demonstrated the effectiveness of BaMet-sEVs in mitigating DOX-induced testicular damage.

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来自nrf2刺激的骨髓间充质干细胞的小细胞外囊泡改善了阿霉素治疗小鼠睾丸损伤和生育障碍。

骨髓间充质/基质干细胞（BMSC）衍生的细胞外小泡（sev）具有低免疫原性和跨越生物屏障的能力，是一种很有前景的治疗药物。阿霉素（DOX）是一种常见的化疗药物，会损害睾丸组织。本研究旨在通过激活骨髓间充质干细胞中的Nrf2基因来增强sev的抗氧化活性，并评估其治疗dox诱导的生育障碍的潜力。DOX诱导NMRI小鼠睾丸损伤。用甲基巴多洛酮（BaMet）处理Wistar大鼠骨髓间充质干细胞，上调Nrf2。通过差示超离心分离sev，并验证其大小、形态和蛋白表达。采用特异性试剂盒测定其抗氧化活性。将含有10 μg蛋白的sev静脉注射到dox损伤小鼠体内。35天后，收集睾丸进行组织病理学、激素和免疫学分析，并评估精子参数。将雄性和雌性小鼠配对以确定怀孕率。在dox损伤小鼠中，bamet - sev表现出更高的抗氧化活性，并显著改善血清睾酮水平、睾丸细胞数量、精子活力和运动性。此外，bamet - sev处理提高了生育能力，增加了后代数量。本研究证明了bamet - sev在减轻dox诱导的睾丸损伤方面的有效性。

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来源期刊

Reproductive toxicology 生物-毒理学

CiteScore

6.50

自引率

3.00%

发文量

131

审稿时长

45 days

期刊介绍： Drawing from a large number of disciplines, Reproductive Toxicology publishes timely, original research on the influence of chemical and physical agents on reproduction. Written by and for obstetricians, pediatricians, embryologists, teratologists, geneticists, toxicologists, andrologists, and others interested in detecting potential reproductive hazards, the journal is a forum for communication among researchers and practitioners. Articles focus on the application of in vitro, animal and clinical research to the practice of clinical medicine. All aspects of reproduction are within the scope of Reproductive Toxicology, including the formation and maturation of male and female gametes, sexual function, the events surrounding the fusion of gametes and the development of the fertilized ovum, nourishment and transport of the conceptus within the genital tract, implantation, embryogenesis, intrauterine growth, placentation and placental function, parturition, lactation and neonatal survival. Adverse reproductive effects in males will be considered as significant as adverse effects occurring in females. To provide a balanced presentation of approaches, equal emphasis will be given to clinical and animal or in vitro work. Typical end points that will be studied by contributors include infertility, sexual dysfunction, spontaneous abortion, malformations, abnormal histogenesis, stillbirth, intrauterine growth retardation, prematurity, behavioral abnormalities, and perinatal mortality.